A selective endothelin ET(A) receptor antagonist, SB 234551, improves cerebral perfusion following permanent focal cerebral ischemia in rats.

Abstract

In recent experimental studies, a selective antagonist of endothelin ET(A) receptors, SB 234551, improved neurological and histological outcome in both head trauma and transient focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect in a model of permanent middle cerebral artery occlusion (MCAo) in rats. Anesthetized Sprague-Dawley rats were subjected to permanent MCAo by insertion of an intraluminal nylon suture coated with poly-L-lysine. The agent (SB 234551, 30 microg/kg/min = 1.8 mg/kg/h) or vehicle (PBS; 0.6 ml/h) was administered by i.v. infusion beginning 15 min after onset of MCAo and lasting for 23.75 h. Autoradiographic measurement of local cerebral blood flow (lCBF) was performed at 24 h. Physiological data were similar among groups. SB 234551 augmented perfusion by 1.7- to 1.8-fold in both the ischemic hemisphere and in the contralateral (non-ischemic) hemisphere when compared to vehicle-treated ischemic animals. In the ischemic hemisphere, the brain regions significantly benefited were those lying outside the zone of most dense ischemia (i.e., paramedian cortex and thalamus), while in the non-ischemic hemisphere all regions measured showed significant lCBF augmentation. This study demonstrates that SB 234551 therapy results in significant improvement of local cerebral perfusion in the ischemic as well as in the non-ischemic hemispheres after permanent MCAo.

• Authors: Yongbo Zhang, Ludmila Belayev, Weizhao Zhao, Elaine A Irving, Raul Busto, Myron D Ginsberg
• Journal: Brain research (Brain Res) Vol. 1045 Issue 1-2 Pg. 150-6 (May 31 2005) ISSN: 0006-8993 [Print] Netherlands
• PMID: 15910773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dioxoles
• Endothelin A Receptor Antagonists
• Pyrazoles
• Receptor, Endothelin A
• SB 234551
• Vasodilator Agents

Topics

• Animals
• Brain (blood supply, drug effects, physiopathology)
• Brain Ischemia (drug therapy, physiopathology, prevention & control)
• Cerebral Arteries (drug effects, physiology)
• Cerebral Infarction (drug therapy, physiopathology, prevention & control)
• Cerebrovascular Circulation (drug effects, physiology)
• Dioxoles (pharmacology)
• Disease Models, Animal
• Endothelin A Receptor Antagonists
• Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
• Male
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (metabolism)
• Treatment Outcome
• Up-Regulation (drug effects, physiology)
• Vasodilator Agents (pharmacology)